tbuckley/cabot-search huggingface dataset:
First-line treatment of unresectable or metastatic HER2 positive esophagogastric adenocarcinoma: liquid biomarker analysis of the phase 2 INTEGA trial
Authors: Lisa Paschold, Alexander Stein, Benjamin Thiele, Joseph Tintelnot, Svenja-Sibylla Henkes, Cornelia Coith, Christoph Schultheiß, Klaus Pantel, Sabine Riethdorf, Mascha Binder
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background The addition of nivolumab to trastuzumab and chemotherapy in first-line unresectable or metastatic HER2 positive esophagogastric adenocarcinoma (HER2+ EGA) results in long progression-free and overall survival as shown by the INTEGA (ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in HER2 positive esophagogastric adenocarcinoma) trial. This trial suggested that the chemotherapy backbone is needed in an unselected HER2+ patient population. Yet, it remains an open question if there are specific patient subsets that may benefit from an enhanced immunotherapeutic but chemotherapy-free approach. Methods We analyzed blood T cell repertoire metrics determined by next-generation sequencing, circulating tumor cell (CTC) counts detected by CellSearch and their expression of HER2 and PD-L1 as potential liquid biomarkers predicting outcomes on ipilimumab versus FOLFOX (folinic acid, FOL, fluorouracil, F, oxaliplatin, OX) chemotherapy added to a backbone of trastuzumab and nivolumab in patients with HER2+ EGA in the INTEGA trial population. Results Patients with two out of three baseline-determined liquid biomarkers—high T cell repertoire richness, absence of CTCs or HER2-expression on CTCs—made up approximately 44% of HER2+ EGA cases and did not show compromise in efficacy if treated with a chemotherapy-free regimen. Long-term responders showing a progression-free survival of &gt;12 months were enriched in this biomarker triad, especially if treated on the chemotherapy-free arm. Conclusion Prospective validation of this liquid biomarker triad is needed to molecularly define HER2+ EGA patient subsets with different needs in the first-line systemic treatment setting.
Tachykinins and the potential causal factors for post-COVID-19 condition
Authors: Sok-Ja Janket, Douglas D Fraser, Alison E Baird, Faleh Tamimi, Dorsa Sohaei, Harry A Conte, Ioannis Prassas, Eleftherios P Diamandis
Journal: The Lancet Microbe (2023)

The most prevalent symptoms of post-COVID-19 condition are pulmonary dysfunction, fatigue and muscle weakness, anxiety, anosmia, dysgeusia, headaches, difficulty in concentrating, sexual dysfunction, and digestive disturbances. Hence, neurological dysfunction and autonomic impairments predominate in post-COVID-19 condition. Tachykinins including the most studied substance P are neuropeptides expressed throughout the nervous and immune systems, and contribute to many physiopathological processes in the nervous, immune, gastrointestinal, respiratory, urogenital, and dermal systems and participate in inflammation, nociception, and cell proliferation. Substance P is a key molecule in neuroimmune crosstalk; immune cells near the peripheral nerve endings can send signals to the brain with cytokines, which highlights the important role of tachykinins in neuroimmune communication. We reviewed the evidence that relates the symptoms of post-COVID-19 condition to the functions of tachykinins and propose a putative pathogenic mechanism. The antagonism of tachykinins receptors can be a potential treatment target.
Long-term health-care utilisation in older patients with cancer and the association with the Geriatric 8 screening tool: a retrospective analysis using linked clinical and population-based data in Belgium
Authors: Victoria Depoorter, Katrijn Vanschoenbeek, Lore Decoster, Geert Silversmit, Philip R Debruyne, Inge De Groof, Dominique Bron, Frank Cornélis, Sylvie Luce, Christian Focan, Vincent Verschaeve, Gwenaëlle Debugne, Christine Langenaeken, Heidi Van Den Bulck, Jean-Charles Goeminne, Wesley Teurfs, Guy Jerusalem, Dirk Schrijvers, Bénédicte Petit, Marika Rasschaert, Jean-Philippe Praet, Katherine Vandenborre, Koen Milisen, Johan Flamaing, Cindy Kenis, Freija Verdoodt, Hans Wildiers
Journal: The Lancet Healthy Longevity (2023)
Multi-layered genetic approaches to identify approved drug targets
Authors: Marie C. Sadler, Chiara Auwerx, Patrick Deelen, Zoltán Kutalik
Journal: Cell Genomics (2023)

Drugs targeting genes linked to disease via evidence from human genetics have increased odds of approval. Approaches to prioritize such genes include genome-wide association studies (GWASs), rare variant burden tests in exome sequencing studies (Exome), or integration of a GWAS with expression/protein quantitative trait loci (eQTL/pQTL-GWAS). Here, we compare gene-prioritization approaches on 30 clinically relevant traits and benchmark their ability to recover drug targets. Across traits, prioritized genes were enriched for drug targets with odds ratios (ORs) of 2.17, 2.04, 1.81, and 1.31 for the GWAS, eQTL-GWAS, Exome, and pQTL-GWAS methods, respectively. Adjusting for differences in testable genes and sample sizes, GWAS outperforms e/pQTL-GWAS, but not the Exome approach. Furthermore, performance increased through gene network diffusion, although the node degree, being the best predictor (OR = 8.7), revealed strong bias in literature-curated networks. In conclusion, we systematically assessed strategies to prioritize drug target genes, highlighting the promises and pitfalls of current approaches.
Gold Nanostars Obviate Limitations to Laser Interstitial Thermal Therapy (LITT) for the Treatment of Intracranial Tumors
Authors: Ethan S. Srinivasan, Yang Liu, Ren A. Odion, Pakawat Chongsathidkiet, Lucas P. Wachsmuth, Aden P. Haskell-Mendoza, Ryan M. Edwards, Aidan J. Canning, Gavin Willoughby, Joseph Hinton, Stephen J. Norton, Christopher D. Lascola, Paolo F. Maccarini, Christopher L. Mariani, Tuan Vo-Dinh, Peter E. Fecci
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Laser interstitial thermal therapy (LITT) is an effective minimally invasive treatment option for intracranial tumors. Our group produced plasmonics-active gold nanostars (GNS) designed to preferentially accumulate within intracranial tumors and amplify the ablative capacity of LITT. Experimental Design: The impact of GNS on LITT coverage capacity was tested in ex vivo models using clinical LITT equipment and agarose gel–based phantoms of control and GNS-infused central “tumors.” In vivo accumulation of GNS and amplification of ablation were tested in murine intracranial and extracranial tumor models followed by intravenous GNS injection, PET/CT, two-photon photoluminescence, inductively coupled plasma mass spectrometry (ICP-MS), histopathology, and laser ablation. Results: Monte Carlo simulations demonstrated the potential of GNS to accelerate and specify thermal distributions. In ex vivo cuboid tumor phantoms, the GNS-infused phantom heated 5.5× faster than the control. In a split-cylinder tumor phantom, the GNS-infused border heated 2× faster and the surrounding area was exposed to 30% lower temperatures, with margin conformation observed in a model of irregular GNS distribution. In vivo, GNS preferentially accumulated within intracranial tumors on PET/CT, two-photon photoluminescence, and ICP-MS at 24 and 72 hours and significantly expedited and increased the maximal temperature achieved in laser ablation compared with control. Conclusions: Our results provide evidence for use of GNS to improve the efficiency and potentially safety of LITT. The in vivo data support selective accumulation within intracranial tumors and amplification of laser ablation, and the GNS-infused phantom experiments demonstrate increased rates of heating, heat contouring to tumor borders, and decreased heating of surrounding regions representing normal structures.
A novel non-invasive exhaled breath biopsy for the diagnosis and screening of breast cancer
Authors: Jiaqi Liu, Haibin Chen, Yalun Li, Yanman Fang, Yang Guo, Shuangquan Li, Juan Xu, Ziqi Jia, Jiali Zou, Gang Liu, Hengyi Xu, Tao Wang, Dingyuan Wang, Yiwen Jiang, Yang Wang, Xuejie Tang, Guangdong Qiao, Yeqing Zhou, Lan Bai, Ran Zhou, Can Lu, Hongwei Wen, Jiayi Li, Yansong Huang, Shuo Zhang, Yong Feng, Hongyan Chen, Shouping Xu, Bailin Zhang, Zhihua Liu, Xiang Wang
Journal: Journal of Hematology & Oncology (2023)

Abstract Background Early detection is critical for improving the survival of breast cancer (BC) patients. Exhaled breath testing as a non-invasive technique might help to improve BC detection. However, the breath test accuracy for BC diagnosis is unclear. Methods This multi-center cohort study consecutively recruited 5047 women from four areas of China who underwent BC screening. Breath samples were collected through standardized breath collection procedures. Volatile organic compound (VOC) markers were identified from a high-throughput breathomics analysis by the high-pressure photon ionization–time-of-flight mass spectrometry (HPPI-TOFMS). Diagnostic models were constructed using the random forest algorithm in the discovery cohort and tested in three external validation cohorts. Results A total of 465 (9.21%) participants were identified with BC. Ten optimal VOC markers were identified to distinguish the breath samples of BC patients from those of non-cancer women. A diagnostic model (BreathBC) consisting of 10 optimal VOC markers showed an area under the curve (AUC) of 0.87 in external validation cohorts. BreathBC-Plus, which combined 10 VOC markers with risk factors, achieved better performance (AUC = 0.94 in the external validation cohorts), superior to that of mammography and ultrasound. Overall, the BreathBC-Plus detection rates were 96.97% for ductal carcinoma in situ, 85.06%, 90.00%, 88.24%, and 100% for stages I, II, III, and IV BC, respectively, with a specificity of 87.70% in the external validation cohorts. Conclusions This is the largest study on breath tests to date. Considering the easy-to-perform procedure and high accuracy, these findings exemplify the potential applicability of breath tests in BC screening.
Identifying Mechanisms of Resistance by Circulating Tumor DNA in EVOLVE, a Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer at Time of PARP Inhibitor Progression
Authors: Stephanie Lheureux, Stephenie D. Prokopec, Leslie E. Oldfield, Eduardo Gonzalez-Ochoa, Jeffrey P. Bruce, Derek Wong, Arnavaz Danesh, Dax Torti, Jonathan Torchia, Alexander Fortuna, Sharanjit Singh, Matthew Irving, Kayla Marsh, Bernard Lam, Vanessa Speers, Aleksandra Yosifova, Ana Oaknin, Ainhoa Madariaga, Neesha C. Dhani, Valerie Bowering, Amit M. Oza, Trevor J. Pugh
Journal: Clinical Cancer Research (2023)

To evaluate the use of blood cell-free DNA (cfDNA) to identify emerging mechanisms of resistance to PARP inhibitors (PARPi) in high-grade serous ovarian cancer (HGSOC).
Abstract 13235: Ischemic Preconditioning and Lazaroid (u-74389g) Administration Similarly Attenuate Ischemia-Reperfusion-Induced Spinal Cord Inflammatory and Apoptotic Responses by Targeting the S100-Receptor for Advanced Glycation End Product Pathway
Authors: James N Tsoporis, Amin Ektesabi, Shehla Izhar, Claudia dos Santos, Thomas G Parker, Howard Leong-Poi, Ioannis K Rizos, Apostolos E Apapalois, Stavros K Toumpoulis, Ioannis K Toumpoulis
Journal: Circulation (2022)

Introduction: Spinal cord injury and subsequent paraplegia represents a devastating complication of thoracoabdominal aortic surgery. Pro-inflammatory cytokine expression and spinal cord neuronal apoptosis have been implicated in inflammation and neurodegeneration respectively after ischemia. Hypothesis: We investigated the neuroprotective effects of the steroid antioxidant Lazaroid U-74389G versus conventional ischemic preconditioning (IPC) in a pig model of spinal cord ischemia-reperfusion injury by examining the expression of pro-inflammatory and pro-apoptotic S100 members and the receptor for advanced glycation end products (RAGE). Methods: Spinal cord ischemia was induced by thoracoabdominal aortic occlusion (TAO). A total of 27 pigs were randomized in four groups. Group I (n=5) sham operation, group II (n=7) TAO for 45min and received placebo, group III (n=8) received 3 doses of Lazaroid (3 mg/kg) 60min and 30min before and at 30min during TAO (duration 45min), and group IV (n=6) TAO for 20min followed by additional TAO for 45min and 80 minutes later. Neurologic evaluation was performed according to Tarlov score (0-4, 4=normal). The lumbar spinal cords were harvested at 7th postoperative day for the expression of inflammatory and apoptotic markers by real-time RT-PCR. Results: Group III and IV had better neurologic outcome postoperatively compared to group II where all animals developed paraplegia (Tarlov scores: 3.5 versus 3.6 versus 0.33, respectively, P&lt;0.001). Group II showed marked pro-inflammatory responses as quantified by 2-4-fold increases in the mRNA of pro-inflammatory S100A6, S100A8 and high-mobility group box 1, and RAGE, compared to group I. Additionally, group II, exhibited apoptosis as quantified by a 40-60% decrease in the mRNA of anti-apoptotic BCL2 and BIRC2, and 2-3-fold increases in pro-apoptotic BAX mRNA and caspase 3 activity. Compared to group II, inflammatory and apoptotic responses were highly attenuated albeit to a similar degree in groups III and IV. Conclusions: In a large animal model very close to the clinical setting, we demonstrated that in addition to IPC, Lazaroid represents an alternative yet effective pharmacologic intervention in reducing spinal cord ischemia-reperfusion injury following TAO.
Abstract 10754: AMPKγ2 Deficiency Exacerbates Macrophage Recruitment and Inflammation Post-MI via Promoting YY1-CXCL16-CXCR6 Axis
Authors: Ziping Song, Dan Liu, Bing Yan, haixu song, Yan Zhang, Yi Cai, Xiaojie Zhao, Xiaoxiang Tian, Chenghui Yan, Yaling Han
Journal: Circulation (2022)

Background: Acute myocardial infarction (MI) has got revolutionized therapeutic strategy by applying timely reperfusion therapy in a particular increase of primary percutaneous coronary intervention. Despite this cardiac remodeling following MI are very common with high mortality. A previous study claimed that AMPK played a pivotal role in intracellular adaptation to energy stress during myocardial ischemia. However, whether AMPKγ2 subunit played an important role in MI remains poorly defined. Hypothesis: We assessed the hypothesis that AMPKγ2 played an important role in regulating MI. Methods: AMPKγ2 level in monocytes of myocardial infarction patients was tested by ELISA. Ligation of left anterior descending branch (LAD) surgery was conducted to establish MI model. Lyz2-cre AMPKγ2 and AAV carrying F4/80 promoter for macrophage-specific overexpression AMPKγ2 mice were employed to investigate the role of AMPKγ2 in macrophages derived from MI. Results: AMPKγ2 was relatively highly expressed in the spleen and macrophage. Lyz2-cre AMPKγ2 mice developed worse cardiac dysfunction post-MI by boosting macrophage infiltration and inflammation. Overexpression of AMPKγ2 in macrophages repressed its migration and inflammation and alleviated myocardial injury. Mechanistically, CXCL16-CXCR6 axis was the contributor to macrophage migration, which was alleviated by AMPKγ2 via transcriptional regulation. Further, AMPKγ2 restrained YY1 expression, a key upstream transcription factor of CXCL16, to block the migration of macrophages. AMPKγ2 promoted YY1 degradation via smurf2 mediating ubiquitin-proteasome pathway depending on AMPKα1 subunit-mediating AMPK activity. Therefore, A769662 but not Metformin alleviated AMPKγ2 deficiency-induced migration and inflammation in macrophages. Finally, IFN-γ downregulated HOXA5 to repress AMPKγ2 transcriptional activity. Consistently, AMPKγ2 was dramatically declined in monocytes of MI patients compared to the control group. Conclusion: Macrophage AMPKγ2 deficiency played an important role in cardiac dysfunction following MI by activating the YY1-CXCL16-CXCR6 axis, which can be developed as a precision therapeutic target to ameliorate cardiac remodeling post-MI.
Abstract 14984: Transient Constrictive Pericarditis: Pericardiectomy to the Rescue
Authors: Alveena B Syed, Zachary S Yaker, Reza Reyaldeen, Alison Krywanczyk, Ankit Agrawal, Muhammad Majid, Ashwin Kumar, Muhammad M Furqan, Abdullah Yesilyaprak, Allan L Klein
Journal: Circulation (2022)

Case Presentation: A 47 years old male presented with progressive dyspnea, bilateral leg and abdominal swelling, weight gain, and intermittent low-grade fever. He had a history of hypertension and chronic lymphocytic pericarditis complicated by an episode of constrictive pericarditis. Exam showed jugular venous pressure of 10 cmH2O, pericardial knock, and abdominal distention. Inflammatory markers were elevated (CRP 87.3 mg/dL, ESR 29 mm/hr). Echo showed abnormal increase in septal longitudinal motion and Doppler interrogation of the hepatic veins showed diastolic flow reversal at the end of expiration. Cardiac MRI showed pericardial thickening and circumferential delayed pericardial enhancement. Patient was diagnosed with transient constrictive pericarditis (TCP) and was treated with ibuprofen, colchicine, and prednisone and had improvement in his symptoms and inflammatory markers. However, he experienced another recurrence 6 months later and underwent pericardiectomy. Pathology showed organized fibrosis overlying the parietal fibrosa layer, mild neovascularization and perivascular chronic inflammation, confirming the diagnosis of TCP. After pericardiectomy, patient had significant symptomatic improvement and returned to his baseline activity level. Postoperative echo showed normalization of annulus longitudinal motion and cardiac MRI showed near resolution of pericardial delayed enhancement. He was successfully tapered off of his anti-inflammatory regimen. Discussion: TCP is a sub-type of constrictive pericarditis characterized by pathological findings of pericardial edema, acute or subacute inflammation, and fibrin deposition, as opposed to the fixed pericardial fibrosis and calcification seen in constrictive pericarditis. Constriction may resolve spontaneously, and anti-inflammatory therapy is the mainstay of treatment but in refractory cases like these, pericardiectomy comes to the rescue.
Abstract 15064: Health Status Profiles in Patients With New or Worsening Peripheral Artery Disease Symptoms and One-Year Hospitalization Risk
Authors: Lindsey Scierka, Clementine Labrosciano, Brooklyn Bradley, Robert Fitridge, John Spertus, Carlos Mena-Hurtado, Kim G Smolderen
Journal: Circulation (2022)

Introduction: Patients with peripheral artery disease (PAD) have an elevated risk of cardiovascular and limb-related events, resulting in increased hospitalizations and costs. In patients with new or worsening PAD symptoms, we used patients’ baseline health status information as a way of identifying patients’ hospitalization. Methods: We included patients enrolled in the United States cohort of the multicenter PORTRAIT Registry from June 2011 and December 2015. PAD-specific health status was assessed at baseline using the Peripheral Artery Questionnaire (PAQ), with scores of 0-100 (higher scores indicating better health status). The primary outcome was 1-year all-cause hospitalizations. The association between PAQ score category (0 to &lt;25, 25 to &lt;50, 50 to &lt;75, and 75-100 used as the reference category) and cumulative hospitalization risk was derived using proportional means models, adjusting for demographics and comorbidities. Results: Of the 797 patients (mean age of 68.6±9.7 years, 41.9% were female), 272 (34%) were admitted over 12 months of follow up. Compared with the best health status (PAQ 75-100), scoring in the lowest health status category (PAQ &lt; 25) was associated with a higher risk of 1-year hospitalization (4.8% vs. 48.6%, adjusted hazard ratio 2.86 [95% confidence interval = 1.61-5.08]). A dose-response relationship was noted for the association between lower health status and increased risk of hospitalization. Similar associations were found for all PAQ domains except symptom stability. Conclusion: In patients with symptomatic PAD, presenting health status profiles were a robust predictor of 1-year hospitalization risk, with a &gt;2-fold difference between those in the lower versus upper scoring segments. Given the potentially modifiable nature of health status, there is a need for monitoring and multicomponent interventions that can improve patients’ health status and potentially also their hospitalization risk.
Abstract 10124: Characteristics of the Right Ventricle in Left Ventricular Noncompaction With Reduced Ejection Fraction
Authors: Zsofia Gregor, Anna Reka Kiss, Kinga Grebur, Zsofia Dohy, Attila Kovacs, Bela Merkely, Hajnalka Vago, Andrea Szucs
Journal: Circulation (2022)

Introduction: Reports of left ventricular noncompaction (LVNC) rarely include descriptions of the right ventricle (RV). Hypothesis: This study aimed to describe the characteristics of the RV in LVNC patients with reduced LV function (LVNC-R) compared with patients with dilated cardiomyopathy (DCM) and subjects with LVNC with normal left ventricular ejection fraction (LV-EF) (LVNC-N). Methods: Forty-four LVNC-R patients, 44 LVNC-N participants, and 31 DCM patients were included in this retrospective study (LV-EF: LVNC-R: 33.4±10.2%; LVNC-N: 65.0±5.9%; DCM: 34.6±7.9%). Each group was further divided into two subgroups by the amount of RV trabeculation. Results: There was no difference in the RV-EF between the groups, and the RV trabecular mass correlated positively with the RV volume and negatively with the RV-EF in all the groups. All the measured parameters were comparable between the groups with decreased LV function. Subgroups with RV hypertrabeculation showed significantly higher RV volumes and lower RV-EF in the decreased-LV-function groups than patients with normal RV trabeculation. LV trabeculation correlated with RV volumes in both noncompacted groups, while the correlation with RV trabeculation was observed only in the LVNC-N group (r=0.469, p=0.001). Both decreased-LV-function groups had worse RV strain values than the LVNC-N group; however, RV strain values correlated with RV trabeculation predominantly in the LVNC-R group. Conclusions: Correlations between LV trabeculation and RV parameters and the presence and characteristics of RV hypertrabeculation raise the possibility of RV involvement in noncompaction; moreover, RV strain values might be helpful in the detection of early subclinical changes of the RV.